Mutant forms of the GTPase KRas have long been recognized as important cancer therapeutic targets. However, measurements made in 1980s and 1990s suggested that GTP bound to KRas so strongly that it could not be disrupted by non-covalently bound small molecules. Across the pharmacopeia, the preponderance of drugs interacts with their targets non-covalently. By 2015, it was widely accepted and reported that KRas was simply undruggable.

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Dr. Hadari’s early drug development career focused on receptor tyrosine kinases – signaling proteins that bind ATP. Reasoning from that experience, Dr. Hadari believed the GTP/KRas affinity measurements were likely flawed.

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In 2015, Dr. Hadari approached Stan Choy and Michael Schmertzler to join him as SHY co-founders. They had previously worked together in the launch for Yale University of an oncology biotech spinoff focused on receptor tyrosine kinases — Michael Schmertzler was the spinoff’s CEO, and Stan Choy, its financial officer. Shortly thereafter, Mark Mitchnick, a long-time collaborator of Mr. Schmertzler’s, joined as a SHY co-founder.

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SHY’s first goal was to test Dr. Hadari’s affinity hypothesis. If updated measurements supported it, the founders intended SHY would seek to develop small molecule inhibitors of multiple targets in the Ras Superfamily of Small GTPases, of which KRas is a member. As in the development of many successful tyrosine kinase inhibitor therapeutics, they reasoned that multi-target Ras Superfamily inhibitors could be more therapeutically effective (yet still safe) if they were not specific just to KRas mutants, but rather, targeted KRas as well as other members of the Ras Superfamily implicated in cancer.

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Using measurement techniques unavailable in the 1980s and 1990s, SHY scientists confirmed Dr. Hadari’s hypothesis – the GTP/KRas interaction they concluded was druggable. In 2020 SHY posted its affinity measurements (Kd’s) on bioRxiv, Cold Spring Harbor Laboratory’s preprint server for biology and, in 2026, published the research in Molecular Cancer Therapeutics. The Kd SHY reported for GTP/KRas and KRas mutant binding was in the range of 250 nM – approximately 10,000 times lower than the estimates published in the 1980s and 1990s.

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After remeasuring the affinity of KRas for GTP, SHY moved on to assemble an intentionally lean, capital-efficient team of experienced bench scientists to develop novel assays and conduct key biological experiments; identified collaborators to undertake high-throughput screens and compound design and synthesis; and an advisory panel of preeminent GTPase scientists.

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Based on computational analyses of physical and in-silico libraries, proprietary high-throughput assays, molecular modeling, and some inspired medicinal chemistry work, SHY has now synthesized a portfolio of over 1,000 small molecules that inhibit or modulate GTP binding to KRas, and other Ras members, by competing non-covalently for GTP binding to their GTP binding sites.

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SHY’s growing patent portfolio reflects its leadership in the development of such non-covalent GTPase inhibitors and modulators.

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Subject to the success of ongoing studies, SHY has a goal of selecting a clinical cancer therapeutic candidate from its multi-target Ras Superfamily of Small GTPases program in late 2026.

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Importantly, building on its success discovering GTPase modulators, SHY has also developed a portfolio of small molecules that inhibit or modulate ATP binding to ATPases. ATP and GTP are biologically significantly distinct molecules but structurally quite similar.

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SHY’s most advanced development program, SHY-ONC6, is being  tested in a Phase 1 clinical trial open to patients with advanced solid tumors.

 

SHY-ONC6 binds selectively to, and inhibits the function of ATPases in the 19S Regulatory Particle of the proteasome. Its mechanism of action is entirely novel and distinct from the mechanism underlying the proteasome inhibitors heretofore approved by the FDA and widely used for the treatment of multiple myeloma and mantle cell lymphoma (tumors of the blood).

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SHY’s anti-infectives program derived from the recognition that, though distinguishable from mammalian types, bacterial and fungal GTPases and ATPases are also central to the function of those organisms. Orally bioavailable compounds in this anti-infectives program demonstrate in vivo and in vitro efficacy comparable to or superior to standards of care against a range of pathogens (including drug resistant strains) that pose serious unmet medical needs.

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The diverse roles of ATPases and GTPases in disease present SHY with many other opportunities to explore the therapeutic potential of its growing expertise and compound portfolios. For now, SHY is focusing its resources on its most advanced programs in oncology and infectious diseases and pursuing only limited proof of principle experiments in other indications. As one example, SHY has pursued exploratory in vivo experiments in a model of a serious neuromuscular disease. After treatment with a SHY compound, diseased tissue was restored to an apparently healthy state.